Previous data suggest that genetic polymorphisms within dopaminergic pathways (i.e., SLC6AC, DRD2, and D4D2) are related to smoking risk. We plan to explore associations of these genes with smoking behavior and exposure (i.e., smoking topography, carbon monoxide and nicotine boost) and resultant harm from tobacco (i.e., carcinogen DNA adducts). Our specific aims are to: (1) compare the harmful biological effects of tobacco smoke exposure in smokers with different genetic predispositions; (2) evaluate whether smoking topography mediates the influences of genetic predisposition on nicotine and carbon monoxide boosts, and the harmful effects of tobacco exposure (i.e., carcinogen- DNA adducts). This will provide support for a mechanism and establish a phenotype of smoking behavior; and (3) explore racial differences in smoking topography and the harmful effects of tobacco smoke exposure. We propose to study approximately 400 population-based smokers, including 200 Caucasians and 200 African Americans in a smoking laboratory. The subjects will smoke two of their own cigarettes, one hour apart, and we will measure smoking topography for the second cigarette. They will undergo an extensive interview and we will determine nicotine and CO boosts, genetic polymorphisms and two different carcinogen- DNA adducts (i.e, BP-dG and 4ABP-dG). This study is important, because it will link genetic predisposition for tobacco addiction to cancer risk by studying smoking behavior. The data also can show the relative contribution on DNA damage of smoking topography and the number of cigarettes smoked per day, and identify which components of smoking topography (e.g., puff duration or volume) most greatly affect carcinogen- DNA adduct formation. We will have new insights into carcinogenic mechanisms due to behavior by using DNA damage as an intermediate biomarker of cancer.